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Cited by 26Liver physiology and pathologyIL-33, ST2, and ILC PathwaysTissue Engineering and Regenerative Medicine

Interleukin‐33 facilitates liver regeneration through serotonin‐involved gut‐liver axis

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Wen, Yankai, Emontzpohl, Christoph, Xu, Long, Atkins, Constance L., Jeong, Jong‐Min, Yang, Yang, Kim, Kangho, Wu, Chuan +2 more·2023·Hepatology
DOI 10.1002/hep.32744PMC PMC10758291
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Abstract

Background and Aims: Insufficient liver regeneration causes post‐hepatectomy liver failure and small‐for‐size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL‐33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL‐33 in liver regeneration after PHx and to elucidate its underlying mechanisms. Approach and Results: We performed PHx in IL‐33 −/− , suppression of tumorigenicity 2 (ST2) −/− , and wild‐type control mice, and found deficiency of IL‐33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be normalized in IL‐33 −/− but not ST2 −/− mice by recombinant murine IL‐33 administration. Furthermore, we observed an increased level of serotonin in portal blood from wild‐type mice, but not IL‐33 −/− or ST2 −/− mice, after PHx. ST2 deficiency specifically in enterochromaffin cells recapitulated the phenotype of delayed liver regeneration observed in ST2 −/− mice. Moreover, the impeded liver regeneration in IL‐33 −/− and ST2 −/− mice was restored to normal levels by the treatment with (±)‐2,5‐dimethoxy‐4‐iodoamphetamine, which is an agonist of the 5‐hydroxytrytamine receptor (HTR)2A. Notably, in vitro experiments demonstrated that serotonin/HTR2A‐induced hepatocyte proliferation is dependent on p70S6K activation. Conclusions: Our study identified that IL‐33 is pro‐regenerative in a noninjurious model of liver resection. The underlying mechanism involved IL‐33/ST2‐induced increase of serotonin release from enterochromaffin cells to portal blood and subsequent HTR2A/p70S6K activation in hepatocytes by serotonin. The findings implicate the potential of targeting the IL‐33/ST2/serotonin pathway to reduce the risk of post‐hepatectomy liver failure and small‐for‐size syndrome.

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  • IL-33 is activated via the ST2 receptor and stimulates serotonin release into portal circulation, promoting hepatocyte proliferation through the HTR2A/p70S6K pathway.

    “IL-33 is activated via the suppression of tumorigenicity 2 (ST2) receptor and stimulates serotonin release into portal circulation. This mechanism promotes hepatocyte proliferation through the 5-Hydroxytryptamine Receptor 2A/Ribosomal Protein S6 Kinase, 70kDa (HTR2A/p70S6K) pathway[65].”

    From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [65]

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Cited by

Sorted by citations

Authors
Wen, Y., Emontzpohl, C., Xu, L., Atkins, C. L., Jeong, J., Yang, Y., Kim, K., Wu, C., Akira, S., & Ju, C.
Affiliations
  • The University of Texas Health Science Center at Houston (US)
  • Anhui Medical University (CN)
  • National Institutes of Health (US)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
Corresponding author
Ju, Cynthia
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2023-04-17
Volume
77
Issue
5
Pages
1580-1592
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.32744
PMC
PMC10758291
OpenAlex
W4296960261
Cited by
26
References
5
Citations by year
2026: 4 · 2025: 8 · 2024: 9 · 2023: 5
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (426793915)
  • National Institutes of Health
  • National Cancer Institute (ZIABC011755)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK122708, R01DK122796, R01DK122708, DK122796, DK121330, R01DK121330)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
IL-33, ST2, liver regeneration, partial hepatectomy, serotonin, gut-liver axis, enterochromaffin cells, HTR2A, p70S6K, hepatocyte proliferation, post-hepatectomy liver failure, small-for-size syndrome, serotonin receptor agonists
MeSH terms
Interleukin-33, Animals, Hepatectomy, Liver, Liver Regeneration, Mice, Inbred C57BL, Serotonin, Liver Failure, Hepatocytes, Ribosomal Protein S6 Kinases, 70-kDa, Gastrointestinal Tract, Cell Proliferation, Mice

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